Field of the Invention
The present invention relates generally to the field of therapeutics for hemostatic disorders.
Background Art
Hemophilia is a bleeding disorder in which blood clotting is disturbed by a lack of certain plasma clotting factors in the coagulation cascade (FIG. 1). Hemophilia A and Hemophilia B are two different types of hemophilia that are caused by deficiencies in Factor VIII (FVIII) and Factor IX, respectively.
Hemophilia A is characterized by spontaneous hemorrhage and excessive bleeding after trauma. Over time, the repeated bleeding into muscles and joints, which often begins in early childhood, results in hemophilic arthropathy and irreversible joint damage. This damage is progressive and can lead to severely limited mobility of joints, muscle atrophy and chronic pain (Rodriguez-Merchan, E. C., Semin. Thromb. Hemost. 29:87-96 (2003), which is herein incorporated by reference in its entirety).
Hemophilia B (also known as Christmas disease) is one of the most common inherited bleeding disorders in the world. It results in decreased in vivo and in vitro blood clotting activity and requires extensive medical monitoring, throughout the life of the affected individual. In the absence of intervention, the afflicted individual will suffer from spontaneous bleeding in the joints, which produces severe pain and debilitating immobility; bleeding into muscles results in the accumulation of blood in those tissues; spontaneous bleeding in the throat and neck can cause asphyxiation if not immediately treated; renal bleeding; and severe bleeding following surgery, minor accidental injuries, or dental extractions also are prevalent.
Treatment of hemophilia is by replacement therapy targeting restoration of Factor VIII and Factor IX activity. Treatment of hemophilia A is by replacement therapy targeting restoration of FVIII activity to 1 to 5% of normal levels to prevent spontaneous bleeding (Mannucci, P. M., et al., N. Engl. J. Med. 344:1773-1779 (2001), which is herein incorporated by reference in its entirety). There are plasma-derived and recombinant FVIII products available to treat bleeding episodes on-demand or to prevent bleeding episodes from occurring by treating prophylactically. Based on the half-life of these products treatment regimens require frequent intravenous administration. Such frequent administration is painful and inconvenient.
Treatment of hemophilia B occurs by replacement of the missing clotting factor by exogenous factor concentrates highly enriched in Factor IX, but is also problematic. Generating such a concentrate from blood is fraught with technical difficulties. Purification of Factor IX from plasma (plasma derived Factor IX; pdFIX) almost exclusively yields active Factor IX. However, such purification of factor IX from plasma is very difficult because Factor IX is only present in low concentration in plasma (5 ug/mL. Andersson, Thrombosis Research 7: 451 459 (1975). Further, purification from blood requires the removal or inactivation of infectious agents such as HIV and HCV. In addition, pdFIX has a short half-life and therefore requires frequent dosing. Recombinant factor IX (rFIX) is also available, but suffers from the same short half-life and need for frequent dosing (e.g., 2-3 times per week for prophylaxis) as pdFIX. rFIX also has a lower incremental recovery (K value) compared to pdFIX, which necessitates the use of higher doses of rFIX than those for pdFIX.
Reduced mortality, prevention of joint damage and improved quality of life have been important achievements due to the development of plasma-derived and recombinant Factor VIII and Factor IX products. Prolonged protection from bleeding would represent another key advancement in the treatment of hemophilia patients. In order to address this need, recombinant Factor VIII and Factor IX proteins expressed as Fc fusions are in development. However, methods of determining appropriate dosage of these products, which have unique pharmacokinetic properties in humans have not yet been developed. Therefore, there remains a need for improved methods of treating hemophilia due to Factor VIII and Factor IX deficiencies that are more tolerable and more effective than current therapies.
Coagulation assays have gained acceptance as an important tool for management of patients being treated for coagulation disorders. These treatments are also applicable to patients on anticoagulation therapy for the prevention of clots in their blood vessels. In these assays, a sample of the patient's blood or plasma is tested for coagulation time or “clotting time” which time is related to the amount of coagulation factors in the patient's blood (or to the patient's dosage of anticoagulant in the case of patients undergoing antocoagulation therapy). Coagulation assays are also required prior to surgical procedures even for patients not suffering from bleeding disorders or on anticoagulation therapy. This is because the medical professionals need to clearly know the bleeding susceptibility before they are operated on.
A variety of coagulation test are presently in use and among the most popular is the “Activated Partial Thromboplastin Time” (aPTT) test (see FIG. 2). Blood coagulation tests have tended to be complex, and the bulk of them are performed generally in centralized clinical laboratories. Clinical or a doctor's office visits or a regular basis to monitor coagulation factor levels can be very inconvenient and expensive. Most of apparatus and methods known for measuring coagulation time in blood samples cannot be used for home testing (see, e.g., U.S. Pat. Nos. 3,695,842; 3,836,333; 4,197,734; 3,486,859; 4,797,369; 3,890,098; 4,725,554; 5,284,624; 3,951,606; 4,659,550; and 5,302,348). The disadvantages of these methods, beside cost and the challenge of operation, include the fact that most do not measure coagulation directly. The large blood volume requirements of some of these methods made them impractical for home use. Many of these methods are also limited by what kinds of coagulation tests they can perform due to the reagent chemistry requirements and the detectable signal generated.